title: Effects of calretinin on Ca2+ signals in cerebellar granule cells: implications of cooperative Ca2+ binding.
abstract: Calretinin is thought to be the main endogenous calcium buffer in cerebellar granule cells (GrCs). However, little is known about the impact of cooperative Ca(2+) binding to calretinin on highly localized and more global (regional) Ca(2+) signals in these cells. Using numerical simulations, we show that an essential property of calretinin is a delayed equilibration with Ca(2+). Therefore, the amount of Ca(2+), which calretinin can accumulate with respect to equilibrium levels, depends on stimulus conditions. Based on our simulations of buffered Ca(2+) diffusion near a single Ca(2+) channel or a large cluster of Ca(2+) channels and previous experimental findings that 150 μM 1,2-bis(o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid (BAPTA) and endogenous calretinin have similar effects on GrC excitability, we estimated the concentration of mobile calretinin in GrCs in the range of 0.7-1.2 mM. Our results suggest that this estimate can provide a starting point for further analysis. We find that calretinin prominently reduces the action potential associated increase in cytosolic free Ca(2+) concentration ([Ca(2+)]( i )) even at a distance of 30 nm from a single Ca(2+) channel. In spite of a buildup of residual Ca(2+), it maintains almost constant maximal [Ca(2+)]( i ) levels during repetitive channel openings with a frequency less than 80 Hz. This occurs because of accelerated Ca(2+) binding as calretinin binds more Ca(2+). Unlike the buffering of high Ca(2+) levels within Ca(2+) nano/microdomains sensed by large conductance Ca(2+)-activated K(+) channels, the buffering of regional Ca(2+) signals by calretinin can never be mimicked by certain concentration of BAPTA under all different experimental conditions.
authors.affiliation: Department of General Physiology of Nervous System, A. A. Bogomoletz Institute of Physiology, Bogomoletz St., 4, Kyiv 01024, Ukraine. esaft@biph.kiev.ua
authors.forename: Elena È
authors.initials: EÈ
authors.lastname: Saftenku
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D064032:Calbindin 2; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology; D002525:Cerebellar Cortex / Q000166:cytology / Q000502:physiology*; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000502:physiology; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism / Q000502:physiology; D051381:Rats; D064030:S100 Calcium Binding Protein G / Q000378:metabolism / Q000502:physiology*
chemical_list: C576512:Calb2 protein, rat; D064032:Calbindin 2; D002135:Calcium-Binding Proteins; D024681:Potassium Channels, Calcium-Activated; D064030:S100 Calcium Binding Protein G